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The Regulation Of Egfr Signaling And Kras Tumorigenesis By Receptor Palmitoylation

Non-Small Cell Lung Cancer (NSCLC) is often characterized by mutually exclusive mutations in epidermal growth factor receptor (EGFR) or KRAS. The mutual exclusivity of these mutations is due to synthetic lethality, revealing a potential therapeutic vulnerability if possible to selectively activate EGFR in KRAS mutant cells. This thesis work demonstrates a previously unidentified mechanism of EGFR signal regulation through palmitoylation, the addition of the 16-carbon palmitate. The palmitoyltransferase, DHHC20, catalyzes this palmitoylation to Cys1025, Cys1122 and Cys1034 on the C-terminal tail of EGFR. Loss of EGFR palmitoylation leads to hyperactivation of the receptor, but decreased cell growth of KRAS mutant cancer cells. While KRAS is still an elusive therapeutic target, here we report that disrupting EGFR palmitoylation by ablation of DHHC20 or expression of a palmitoylation-resistant EGFR mutant blocks tumorigenesis in a KRAS-driven mouse model of lung adenocarcinoma. Mechanistically, we show that in the presence of oncogenic KRAS, unpalmitoylated, active EGFR increases signaling through the MAP Kinase pathway while simultaneously reducing PI3K/AKT signaling leading to a severe decrease in expression of the central proliferation-associated transcription factor, Myc, similarly as impossible to therapeutically target as KRAS. We find that the dysregulation of EGFR palmitoylation from DHHC20 loss disrupts the delicate balance of MAPK and PI3K signaling leading to detrimental loss of Myc expression and subsequent loss of cell growth. Initially, we discovered that inhibiting EGFR palmitoylation increases sensitivity to the EGFR tyrosine kinase inhibitor, gefitinib, in cell lines specifically harboring mutant KRAS and interestingly, in cells harboring the drug-resistant EGFR gatekeeper mutation through a mechanism that is still unclear. We have now determined that inhibition of DHHC20 induces sensitivity of KRAS mutant cells to a clinically available pan-PI3K inhibitor, Buparlisib, more effective than gefitinib in inducing cell death by directly blocking the residual, necessary PI3K signaling. Thus, this previously unappreciated mechanism of receptor signaling modulation driven by the palmitoyltransferase, DHHC20, can be exploited to treat the currently incurable mutant KRAS NSCLCs

Adipokines: mediators of immunity and inflammation

White adipose tissue has emerged as a highly dynamic organ that releases a plethora of immune and inflammatory mediators that are involved in obesity, metabolic syndrome and immune mediated diseases. Adipokines have complex role in various physiological and pathological processes by exerting potent modulatory actions on target tissues In this Review, In this review, we explore the effects of different adipokines, focusing primarily on leptin, adiponectin, visfatin and resistin in causing immune-mediated and/or inflammatory diseases

Hypercalcemia and Milk Alkali Syndrome: A Case Report

A triad of metabolic alkalosis, hypercalcemia and renal insufficiency constitutes the milk alkali syndrome. Elderly subjects, especially those on drugs that GFR are more prone to acquire this syndrome. Those who take calcium supplements have high chances of developing milk alkali syndrome and this stands amongst the top five causes of hypercalcemia. Herein we present a case of hypercalcemia who was taking only small amount of calcium supplements but had a few concomitant risk factors

Coprecipitation of Radio Ruthenium with Hydrous Manganese Dioxide

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On-demand Server-less Log Multiplexer for Single-Container Processes

In single-container processes, which limit the number of compute processes per container, the capture and transmission of logs can become infeasible because a separate, disk-based, log-capture and emission process is disallowed. This disclosure describes a log multiplexer that uses memory-multiplexing techniques to transport logs to multiple destinations within a single-container process. The log multiplexer interfaces with an in-memory, single process, shim layer that encompasses a generic, single-container application, becoming a single-point pipe pass-through for all emitted logs. Based on a static or a dynamic configuration provided to the application, the single-point pass-through multiplexer determines the endpoints where the logs are to be redirected. Acting as a pass-through multiplexer for logs within single-process memory, the logger enables fast and dynamic log emission to multiple endpoints

TARGETING THE MUC1-C ONCOPROTEIN DOWNREGULATES HER2 ACTIVATION AND ABROGATES TRASTUZUMAB RESISTANCE IN BREAST CANCER CELLS

Patients with HER2 positive breast cancer often exhibit intrinsic or acquired resistance to trastuzumab treatment. The transmembrane MUC1-C oncoprotein is aberrantly overexpressed in breast cancer cells and associates with HER2. The present studies demonstrate that silencing MUC1-C in HER2-overexpressing SKBR3 and BT474 breast cancer cells results in downregulation of constitutive HER2 activation. Moreover, treatment with the MUC1-C inhibitor, GO-203, was associated with disruption of MUC1-C/HER2 complexes and decreases in tyrosine phosphorylated HER2 (p-HER2) levels. In studies of trastuzumab-resistant SKBR3R and BT474R cells, we found that the association between MUC1-C and HER2 is markedly increased (~20-fold) as compared to that in sensitive cells. Additionally, silencing MUC1-C in the trastuzumab-resistant cells or treatment with GO-203 decreased p-HER2 and AKT activation. Moreover, targeting MUC1-C was associated with downregulation of phospho-p27 and cyclin E, which confer trastuzumab resistance. Consistent with these results, targeting MUC1-C inhibited the growth and clonogenic survival of both trastuzumab-resistant cells. Our results further demonstrate that silencing MUC1-C reverses resistance to trastuzumab and that the combination of GO-203 and trastuzumab is highly synergistic. These findings indicate that MUC1-C contributes to constitutive activation of the HER2 pathway and that targeting MUC1-C represents a potential approach to abrogate trastuzumab resistance